Flumazenil (chemically named ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate), also known as, Ro 15-1788, Anexate™, Lanexat™, Mazicon™ and Romazicon™, was initially disclosed in U.S. Pat. No. 4,316,839. Flumazenil is an imidazobenzodiazepine having high affinity for the GABAA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. As flumazenil is a competitive inhibitor of benzodiazepines, it is used for reversing benzodiazepine-induced sedation and anesthesia following therapeutic or diagnostic procedures (e.g. WO 2009/114740). Flumazenil is also known to reverse the effect of non-benzodiazepine drugs, such as the imidazopyridine hypnotic zolpidem (e.g. Patat et al., Clin Pharmacol Ther., 1994, 56(4):430-6). Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypontic) (Bond A J, 1998, CNS Drugs, 9(1): 41-57). Flumazenil is also effective in treating hepatic encephalopathy (Als-Nielsen B et al. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD002798. DOI: 10.1002/14651858.CD002798.pub2). The aforementioned therapeutic effects were achieved by intravenous administration of flumazenil in a liquid formulation.
A liquid formulation of flumazenil (Romazicon®) is currently approved for reversing the sedative effects of benzodiazepines. Due to the limited solubility of flumazenil, the Romazicon® liquid formulation contains only 0.01% flumazenil. Poor water solubility frequently correlates with low drug absorption and bioavailability, and limits the amount of drug that can be administered in a pharmaceutical composition.
The use of hydrotopes, such as nicotinamide, for complexation with insoluble compounds in order to improve their solubility is known, for example, U.S. Pat. No. 6,087,353.
There remains an unmet need to formulate flumazenil derivatives that are highly soluble and thereby suitable for the preparation of highly concentrated flumazenil formulations.